A therapeutic antibody is a protein that attaches to a defined
molecule on the surface of a cell. These agents can exert
anticancer effects in several different ways. For example, they can
block cancer-driving signaling networks initiated by the specific
molecule to which they attach, and they can work by attaching to
cancer cells expressing their target, flagging them for destruction
by the immune system. Therapeutic antibodies that flag cells for
the immune system are a form of molecularly targeted
immunotherapy, and they include an experimental medicine,
called Ch14.18, that is showing promise as a treatment for
high-risk neuroblastoma.

Immunotherapy with Ch14.18, in combination with two factors that
also boost the killing power of the immune system, has been
shown in clinical trials to increase dramatically—by 20 percentage
points—the chance that a child with high-risk neuroblastoma will
be cancer free two years later (109). Although this treatment
strategy is not FDA approved, it is at the forefront of care for a
group of patients who have a tremendous need for new treatment
options; fewer than one in every two children diagnosed with high-risk neuroblastoma live five years (110).

Despite the tremendous success of the Ch14.18 combination
immunotherapy, which is enabling some children, like Brooke
Mulford, to live disease free, the treatment is associated with
significant toxicities. They can be so severe that some children
cannot complete the treatment course, while those who do, suffer
lasting negative side effects. Ongoing basic and clinical research is
seeking ways to mitigate these severe side effects as well as to
identify those children most likely to benefit from treatment or
those least likely to respond, so that the latter can be spared from
futile and potentially noxious therapies.

A New Day for Patient Stratification

The rapid pace of scientific and technological innovation over the
past few decades has made it possible to link specific genetic
mutations to distinct behaviors of individual cancers. As a result,
we now have the ability to understand that two patients with what
is described clinically as a single disease, say lung cancer, may
actually have two completely different cancers at the molecular
level. Thus, these patients may have two very distinct courses of
disease over time, and will therefore require entirely different
molecularly targeted drugs (see Fig. 19, p. 67).

Our arsenal of precisely targeted cancer drugs is expanding each
year. However, the effective therapeutic use of these drugs often
requires a test, called a companion diagnostic, that can accurately
match patients with the most appropriate therapies. Patients
positively identified by the test can rapidly receive a treatment to
which they are very likely to respond. Those patients identified as
very unlikely to respond can be spared any adverse side effects of
the therapy and immediately start an alternative treatment, saving
them precious time in their race to find an effective therapy.
Moreover, definitive stratification of patient populations can also
provide substantial health care savings by avoiding the deployment
of ineffective courses of cancer treatments and the treatment costs
associated with their adverse effects.

Many molecularly targeted cancer drugs have been FDA approved
without a companion diagnostic. In August 2011, however, the FDA
approved a drug/test pair that is now benefiting a defined group of
lung cancer patients. The drug, crizotinib (Xalkori), blocks the
signaling molecule ALK. It was developed after fundamental
research established that genetic aberrations that lead to altered
ALK expression and activity drive some lung cancers. Crizotinib
dramatically improves the survival of patients with ALK gene
defects, like Monica Barlow, p. 66 (111). However, these
individuals make up fewer than 7% of all patients diagnosed with
the most common form of lung cancer, non-small-cell lung cancer.
Without the companion diagnostic, this small population of patients
would not be identified, making crizotinib clinically useless because
the patient and financial costs would far outweigh the benefits.

The success of crizotinib and the importance of its companion
diagnostic emphasize the value of having a way to identify those
patients with a high likelihood of responding to a particular drug,
and many molecularly targeted drugs for cancer treatment are now
being developed side-by-side with a companion diagnostic.

Additional clinical tests to divide patients with a given cancer into
therapy groups based on the molecular characteristics of their
individual cancers are urgently needed because not all patients
with a given genetic defect will benefit from a drug targeting that
alteration. For example, while genetic alterations that result in
cancers driven by a specific cell surface protein called EGFR are
found in 10% of non-small-cell lung cancers (112) and in almost